Air pollutants/irritants evoke dangerous sympathoexcitatory reflexes in individuals with cardiovascular disease (CVD) but evoke sympathoinhibitory reflexes in healthy subjects. However, there is a major gap in understand- ing how irritant-evoked pulmonary-cardiac reflexes are remodeled in CVD. This is significant because it is the reflex remodeling that determines the impact of pollution and thus the fundamental cause of acute pollutant- evoked cardiovascular (CV) events, which are responsible for >100k US deaths annually. Thus, there are no clinical options to identify or treat at-risk individuals. Irritants trigger pulmonary-cardiac reflexes via the activa- tion of airway afferent nerves that express transient receptor potential (TRP) ankyrin 1 and vanilloid 1. TRPs are typically expressed on C- but not A-fibers, which can trigger parasympathetic and sympathetic reflexes, respectively. The long-term goal is a complete understanding of the mechanisms and networks responsible for the aberrant pulmonary-cardiac reflexes in CVD. The objective here is to determine the specific afferent and efferent signaling evoked by airway TRP activation in two CVD rat models and determine the mechanistic cause of the CVD-linked reflex remodeling. The central hypothesis, based upon strong preliminary data, is that aberrant irritant-evoked reflexes in CVD are due to de novo recruitment of sympathetic nerves downstream of chronic remodeling of TRP-expressing airway afferent networks. The hypothesis is innovative because this is the first time that the basis of the pathophysiology, the remodeling of pulmonary-cardiac reflexes, has been targeted. Aim 1: Identify the autonomic efferent pathways responsible for the remodeled airway irritant-evoked reflexes in CVD. It is hypothesized that CVD switches irritant-evoked pulmonary-cardiac reflexes from para- sympathetic-mediated bradycardia towards tachyarrhythmia due to de novo recruitment of cardiac sympathetic nerves. Aim 2: Determine the airway afferent signaling required for the remodeled irritant-evoked pulmonary- cardiac reflexes in CVD. It is hypothesized that irritant-evoked sympathoexcitation in CVD is due to de novo expression of TRPs in airway A-fiber afferents. Aim 3: Determine the mechanism underlying the remodeling of pulmonary-cardiac reflexes in CVD. It is hypothesized that reflex remodeling is due to renin-angiotensin system (RAS) activation and so will be sensitive to RAS inhibition but not to other antihypertensives. This study is sig- nificant because it is an absolute requirement for the refinement of pharmacological and electroceutical thera- pies to treat pollution-induced CV events; the identification of novel targets critical to the CVD-induced reflex remodeling; and the development of biomarkers for at-risk individuals with altered pulmonary-cardiac reflexes. The approach is innovative because mechanisms will be studied free of anesthetics, which alter pulmonary- cardiac reflexes, using state-of-the-art electrophysiological techniques. Thus, these studies will have a trans- formative impact upon our understanding of irritant-evoked reflexes, and are expected to lead to a paradigm shift in our approach to reduce the impact of aberrant airway reflexes on the clinical population.